Compositions and methods for contraception and for treatment of benign gynecological disorders

Abstract

Compositions and methods for use in preventing conception or treating benign gynecological disorders, wherein an effective amount of an antiprogestational agent [e.g., progesterone (progestin, progestogen, gestagen) antagonist or progesterone synthesis inhibitor] administered over a first period of time is combined with an effective amount of a progestogen for a second period of time. The antiprogestational agent is selected from single agents or mixtures thereof. The progestogen is selected from single agents or mixtures of natural or synthetic progestogens. The formulations are effective as contraceptive agents and for treatment of benign gynecological disorders including uterine fibroids, premenstrual syndrome, dysfunctional uterine bleeding, polycystic ovarian syndrome and endometriosis.

What is claimed is:  
     
       1. A method for preventing conception comprising: 
       administering an antiprogestational agent, at a level effective to inhibit ovulation, over a first period of time of about six weeks to about twenty-six weeks; and  
       administering a progestational agent, at a level effective to inhibit endometrial proliferation, over a second period of time of about five to about twenty-one days immediately following, immediately preceding, or running concurrently with a portion of said first period of time.  
     
     
       2. A method according to claim  1 , wherein said progestational agent is selected from the group consisting of dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, megesterol acetate, gestodene, desogestrel, cingestol, lynestrenol, quingestanol acetate and chlormadinone. 
     
     
       3. A method according to claim  1 , wherein said first period of time is about two months to about three months. 
     
     
       4. A method according to claim  1 , wherein said second period of time is about ten days to about fifteen days. 
     
     
       5. A method according to claim  1 , wherein the second period of time is less than thirty percent of the first period of time. 
     
     
       6. A method according to claim  1 , wherein the second period of time immediately follows or immediately precedes the first period of time. 
     
     
       7. The method of claim  1  wherein said first period of time is about two to about three months, and said second period of time is about ten days to about fifteen days. 
     
     
       8. A method according to claim  1 , wherein the antiprogestational agent is selected from the group consisting of mifepristone, onapristone, 11-4(4-acetylphenyl)-17-hydroxy-17-(propynyl)-9-diene-3-one, (6α,11β,17β)-11-(4-NMe 2 -phenyl)-6-Me-4′,5′-dihydrospiro[oestra-4,9-diene-17,2′(3′H)-furan]-3-one, (11β,17α)-11-(4- acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one, (7β,11β,17β)-11-(4-(NMe 2 -phenyl)-7- Me-4′,5′-dihydrospiro(oestra-4,9-diene-17,2′(3′H)-furan)-3-one, lilopristone, trilostane, epostane, azastene and cyanoketone. 
     
     
       9. A method according to claim  8 , wherein said antiprogestational agent is selected from the group consisting of mifepristone, onapristone, and 11-4(4-acetylphenyl)-17-hydroxy-17-(-propynyl)-, 9-diene-3-one. 
     
     
       10. A method for treating a non-malignant gynecological disorder where suppression of ovulation and/or suppression of ovarian progesterone production is therapeutic, the method comprising: 
       administering an antiprogestational agent, at a level effective to inhibit ovulation, over a first period of time of about six weeks to about twenty-six weeks; and  
       administering a progestational agent, at a level effective to inhibit endometrial proliferation, over a second period of time of about five to about twenty-one days immediately following, immediately preceding, or running concurrently with a portion of said first period of time.  
     
     
       11. A method according to claim  10 , wherein the progestational agent is selected from the group consisting of dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, megesterol acetate, gestodene, desogestrel, cingestol, lynestrenol, quingestanol acetate and chlormadinone. 
     
     
       12. A method according to claim  10 , wherein the antiprogestational agent is selected from the group consisting of mifepristone, onapristone, 11-4(4-acetylphenyl)-17-hydroxy-17-(propynyl)-9- diene-3-one, (6α,11β,17β)-11-(4-NMe 2 -phenyl)-6-Me-4′,5′-dihydrospiro -3-one, (11β,17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one, (7β,11β,17β)-11-(4-(NMe 2 -phenyl)-7-Me-4′,5′-dihydrospiro(oestra-4,9-diene-17,2′(3′H)-furan)-3-one, lilopristone, trilostane, epostane, azastene and cyanoketone. 
     
     
       13. A method according to claim  10 , wherein the first period of time is about two months to about three months. 
     
     
       14. A method according to claim  10 , wherein the second period of time is about ten days to about fifteen days. 
     
     
       15. A method for treating a non-malignant gynecological disorder, comprising: 
       administering an antiprogestational agent, at a level effective to inhibit ovulation, over a first period of time of about six weeks to about twenty-six weeks; and  
       administering a progestational agent, at a level effective to inhibit endometrial proliferation, over a second period of time of about five to about twenty-one days immediately following, immediately preceding, or running concurrently with a portion of said first period of time;  
       wherein the benign gynecological disorder is selected from the group consisting of uterine fibroids, premenstrual syndrome, dysfunctional uterine bleeding, polycystic ovarian syndrome and endometriosis.  
     
     
       16. The method of claim  15  wherein said first period of time is about two to about three months, and said second period of time is about ten days to about fifteen days. 
     
     
       17. A method for treating a non-malignant gynecological disorder, comprising: 
       administering an antiprogestational agent, at a level effective to inhibit ovulation, over a first period of time of about six weeks to about twenty-six weeks; and  
       administering a progestational agent, at a level effective to inhibit endometrial proliferation, over a second period of time of about five to about twenty-one days immediately following, immediately preceding, or running concurrently with aportion of said first period of time;  
       wherein the benign gynecological disorder is selected from the group consisting of uterine fibroids, premenstrual syndrome, dysfunctional uterine bleeding, and polycystic ovarian syndrome.  
     
     
       18. The method of claim  17  wherein said first period of time is about two to about three months, and said second period of time is about ten days to about fifteen days. 
     
     
       19. A method for suppressing ovulation and/or ovarian progesterone production comprising: 
       administering an antiprogestational agent, at a level effective to inhibit ovulation, over a first period of time of about six weeks to about twenty-six weeks; and  
       administering a progestational agent, at a level effective to inhibit endometrial proliferation, over a second period of time of about five to about twenty-one days immediately following, immediately preceding, or running concurrently with a portion of said first period of time.  
     
     
       20. A method according to claim  19 , wherein the progestational agent is selected from the group consisting of dydrogesterone, ethynodiol diacetate, hydroxyprogesterone caproate, medroxyprogesterone acetate, norethindrone, norethindrone acetate, norethynodrel, norgestrel, progesterone, megesterol acetate, gestodene, desogestrel, cingestol, lynestrenol, quingestanol acetate and chlormadinone. 
     
     
       21. A method according to claim  19 , wherein the antiprogestational agent is selected from the group consisting of mifepristone, onapristone, 11-4(4-acetylphenyl)-17-hydroxy-17-(propynyl)-9- diene-3-one, (6α,11β,17β)-11-(4-NMe 2 -phenyl)-6-Me-4′,5′-dihydrospiro[oestra-4,9-diene-17,2′(3′H)- furan]-3-one, (11β, 17α)-11-(4-acetylphenyl)-17,23-epoxy-19,24-dinorchola-4,9,20-trien-3-one, (7β,11β,17β)-11-(4-(NMe 2 -phenyl)-7-Me-4′,5′-dihydrospiro(oestra-4,9-diene-17,2′(3′H)-furan)-3-one, lilopristone, trilostane, epostane, azastene and cyanoketone. 
     
     
       22. A method according to claim  19 , wherein the first period of time is about two months to about three months. 
     
     
       23. A method according to claim  19 , wherein the second period of time is about ten days to about fifteen days.